Medulloblastoma (MB), a tumor that arises in the cerebellum, is the most common malignant brain tumor of childhood, yet little is known about the genetic element(s) that is(are) involved in either MB development or progression. A possible genetic basis for MB has been established by the identification of mutations in the adenomatous polyposis coli (A PC) gene in patients that have a predisposition for colon carcinoma coupled with a significantly greater than average incidence of neuroepithelial neoplasias. APC is a tumor suppressor commonly altered in familial and sporadic colon carcinoma, but its role in MB has not been fully investigated. Mutations in APC gene exons 1-15 have not been found, thus far, to correlate with MB. Dr. Joanna Groden, this applications' cosponsor, has identified four novel 5' exons in the APC gene that give rise to eight APC isoforms that predominate in brain, however, giving rise to the possibility that brain tumors result from mutations in 5' exons. Moreover, in collaboration with Dr. Groden, we have found that MB cell lines do not express the 5' exon-containing APC isoforms. This proposal is focused on identifying which APC isoforms are expressed in normal developing and adult cerebellum and which, consistently, are lost in MB. Isoforms that characterize normal cerebellum, but not MB, will be transfected into MB cell lines to determine if their expression alters the invasiveness or tumorigenicity of MB. Finally, will characterize proteins that interact with proteins encoded by the 5' APC exons in efforts to determine by what mechanism APC may act as a tumor suppressor in cells of the nervous system.